Use of prodrugs of fumarates in treating heart failure diseases

ABSTRACT

Methods and pharmaceutical compositions comprising one or more prodrugs (e.g., aminoalkyl prodrugs) of monomethyl fumarate (MMF) thereof are provided herein for the treatment of a heart failure disease, including heart failure with preserved ejection fraction. The compounds of the present disclosure are configured to be converted in vivo, upon oral administration, to monomethyl fumarate. Upon conversion, the active moiety (i.e., monomethyl fumarate) of various embodiments is effective in treating subjects suffering from a heart failure disease, including heart failure with preserved ejection fraction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to U.S. provisional patentapplication Ser. No. 62/210,730, filed on Aug. 27, 2015, which is hereinincorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety, as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference in its entirety.

TECHNICAL FIELD

This disclosure relates to methods and compositions of treating heartfailure diseases, including heart failure with preserved ejectionfraction, in a subject in need thereof by administering to the subject atherapeutically effective amount of one or more prodrugs of monomethylfumarate (MMF) alone or in combination with one or more second agentsuseful for treating heart failure.

BACKGROUND

Heart failure (HF) is major health problem in the United States (U.S.)and elsewhere. In the U.S., HF affects over 5 million people withapproximately half a million new cases occurring each year. HF is theleading cause of hospitalizations in people over 65 years in age. HF hasmany potential causes and diverse clinical features. Symptoms of heartfailure can include dyspnea during activity or at rest, cough with whitesputum, rapid weight gain, swelling in ankles, legs and abdomen,dizziness, fatigue and weakness, rapid or irregular heartbeats, nausea,palpitations, and chest pains.

About half of heart failure patients have heart failure with preservedejection fraction (HFPEF). Distinct from traditional HF, i.e., heartfailure with reduced ejection fraction (HFREF) in which the ventriclecannot properly contract, patients with HFPEF show declined performanceof a heart ventricle, not at the time of contraction (systole), butduring the phase of filling (diastole). HFPEF patients show normalejection fraction of blood pumped out of the ventricle, but the heartmuscle does not quickly relax to allow efficient filling of bloodreturning from the body. Morbidity and mortality of HFPEF are similar toHFREF; however, therapies that benefit HFREF are not effective intreating or preventing HFPEF. Patients with HFPEF have an ejectionfraction of ≥40%, ≥45%, or ≥50% depending on which definition is chosenfrom the literature. On the other hand, patients with HFREF have anejection fraction of either ≤35% or ≤40% depending on which definitionand guidelines are used. For ease of simplicity, and not to be limitingin any way, HFPEF can be considered as having an ejection fraction ≥40%and HFREF can be considered as having an ejection fraction <40%.

Other names for the two primary clinical subsets of HF are diastolicheart failure (DHF) and systolic heart failure (SHF). SHF, which is alsoknown as heart failure with reduced ejection fraction (HFREF), involvesan abnormality of the heart resulting in failure of the heart to pumpblood at a rate needed for metabolizing tissues at rest and/or duringexertion. DHF, which is also known as heart failure with preservedejection fraction (HFPEF), is a clinical syndrome with symptoms andsigns of HF, a preserved ejection fraction, and abnormal diastolicfunction. The clinical manifestations of HFREF and HFPEF have distinctdifferences in risk factors, patient characteristics, andpathophysiology. Moreover, medications proven effective in HFREF havenot been found to be effective in HFPEF. At present there are noapproved treatments to reduce mortality in HFPEF.

In HFREF, medications such as beta-blockers, ace-inhibitors, angiotensinreceptor blockers, isosorbide dinitrate, hydralazine, aldosteroneinhibitors, and angiotensin receptor neprilysin inhibitors have beenshown to provide benefit. However, these medications have not shown tobe beneficial in patients with HFPEF, and are not approved therapies forHFPEF.

Given that there are currently no approved treatments to improvesurvival in HFPEF, there remains, therefore, an urgent need in thetreatment of HFPEF for a product that can improve morbidity andmortality of patients with HFPEF.

The present disclosure addresses the needs in patients with HFPEF aswell as in patients at risk of developing HFPEF, due to conditionsincluding but not limited to hypertension, diabetes, COPD, atrialfibrillation, or ischemic heart disease.

Fumaric acid esters (FAEs) are approved in Germany for the treatment ofpsoriasis, are being evaluated in the United States for the treatment ofpsoriasis and multiple sclerosis, and have been proposed for use intreating a number of immunological, autoimmune, and inflammatorydiseases and conditions.

FAEs and other fumaric acid derivatives have been proposed for use intreating a wide-variety of diseases and conditions involvingimmunological, autoimmune, and/or inflammatory processes includingpsoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882;Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdiand Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronicobstructive pulmonary diseases (Joshi et al., WO 2005/023241 and U.S.2007/0027076); mitochondrial and neurodegenerative diseases such asParkinson's disease, Alzheimer's disease, Huntington's disease,retinopathia pigmentos, and mitochondrial encephalomyopathy (Joshi andStrebel, WO 2002/055063, U.S. 2006/0205659, U.S. Pat. No. 6,509,376,U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423); transplantation(Joshi and Strebel, WO 2002/055063, U.S. 2006/0205659, U.S. Pat. No.6,359,003, U.S. Pat. No. 6,509,376, and U.S. Pat. No. 7,157,423; andLehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmunediseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. No. 6,509,376,U.S. Pat. No. 7,157,423, and U.S. 2006/0205659) including multiplesclerosis (MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No.6,436,992; Went and Lieberburg, U.S. 2008/0089896; Schimrigk et al., EurJ Neurology 2006, 13, 604-610; and Schilling et al., Clin ExperimentalImmunology 2006, 145, 101-107); ischemia and reperfusion injury (Joshiet al., U.S. 2007/0027076); AGE-induced genome damage (Heidland, WO2005/027899); inflammatory bowel diseases such as Crohn's disease andulcerative colitis; arthritis; and others (Nilsson et al., WO2006/037342 and Nilsson and Muller, WO 2007/042034).

FUMADERM®, an enteric coated tablet containing a salt mixture ofmonoethyl fumarate and dimethyl fumarate (DMF) which is rapidlyhydrolyzed to monomethyl fumarate, regarded as the main bioactivemetabolite, was approved in Germany in 1994 for the treatment ofpsoriasis. FUMADERM® is dosed three times daily (TID) with 1-2 grams/dayadministered for the treatment of psoriasis. FUMADERM® exhibits a highdegree of interpatient variability with respect to drug absorption, andfood strongly reduces bioavailability. Absorption is thought to occur inthe small intestine with peak levels achieved 5-6 hours after oraladministration. Significant side effects occur in 70-90% of patients(Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; andHoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects ofcurrent FAE therapy include gastrointestinal upset including nausea,vomiting, diarrhea, and/or transient flushing of the skin.

Dimethyl fumarate (DMF) is the active component of BG-12, also known asTecfidera®, studied for the treatment of relapsing-remitting MS (RRMS).In a Phase IIb RRMS study, BG-12 significantly reducedgadolinium-enhancing brain lesions. In preclinical studies, DMFadministration has been shown to inhibit central nervous system (CNS)inflammation in murine and rat experimental autoimmune encephalomyelitis(EAE). It has also been found that DMF can inhibit astrogliosis andmicroglial activations associated with EAE. See, e.g., U.S. PublishedApplication No. 2012/0165404.

Despite its benefits, dimethyl fumarate is also associated withsignificant drawbacks. For example, dimethyl fumarate is known to causeside effects upon oral administration, such as flushing andgastrointestinal events including, nausea, diarrhea, and/or upperabdominal pain in subjects. See, e.g., Gold et al., N. Eng. J. Med.,2012, 367(12), 1098-1107. Dimethyl fumarate is dosed twice daily (BID)or TID with a total daily dose of about 480 mg to about 1 gram or more.

Further, in the use of a drug for long-term therapy, it is desirablethat the drug be formulated so that it is suitable for once- ortwice-daily administration to aid patient compliance. A dosing frequencyof once-daily or less is even more desirable.

Another problem with long-term therapy is the requirement of determiningan optimum dose, which can be tolerated by the patient. If such a doseis not determined, this can lead to a diminution in the effectiveness ofthe drug being administered.

Accordingly, it is an object of the present disclosure to providecompositions, which are suitable for long-term administration forpatients in need of therapy of heart failure disease, including heartfailure with preserved ejection fraction.

It is a further object of the present disclosure to provide the use of apharmaceutically active agent in a manner which enables one to achieve atolerable steady state level of the drug in a subject being treatedtherewith.

Because of the disadvantages of dimethyl fumarate described above, therecontinues to be a need to decrease the dosing frequency, reduceside-effects, and/or improve the physicochemical properties associatedwith DMF. There remains, therefore, a real need in the treatment ofcertain conditions for a product that retains the pharmacologicaladvantages of DMF but overcomes its flaws in formulation and/or adverseeffects upon administration. The present disclosure addresses theseneeds in patients with heart failure disease.

SUMMARY

The present disclosure relates to methods and compositions useful in thetreatment of heart failure diseases. The methods and compositionsdescribed herein comprise one or more prodrugs (e.g., aminoalkylprodrugs) of monomethyl fumarate (MMF) for the treatment of a heartfailure disease. In some embodiments, heart failure disease is heartfailure with preserved ejection fraction (HFPEF).

More specifically, the compounds of the disclosure can be converted invivo, upon oral administration, to monomethyl fumarate. Upon conversion,the active moiety (i.e., monomethyl fumarate) is effective in treatingsubjects suffering from a heart failure disease.

Prodrugs of monomethyl fumarate refer to compounds described in U.S.Pat. No. 8,669,281, which is herein incorporated by reference in itsentirety, having, in part, a compound of Formula (I), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof:

wherein:

R₁ is unsubstituted C₁-C₆ alkyl;

L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker, substituted orunsubstituted C₃-C₁₀ carbocycle, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted heterocycle comprising one or two 5-or 6-member rings and 1-4 heteroatoms selected from N, O and S, orsubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S; and

R₂ and R₃ either:

(a) are each, independently, H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₆-C₁₀ aryl,substituted or unsubstituted C₃-C₁₀ carbocycle, substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S; or alternatively,

(b) form, together with the nitrogen atom to which they are attached, asubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S or asubstituted or unsubstituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

In one embodiment of the present disclosure, one or more prodrugs ofmonomethyl fumarate comprise a compound having the formula:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides pharmaceutical compositionscomprising one or more compounds of any of the formulae described inU.S. Pat. No. 8,669,281, the disclosure of which is herein incorporatedby reference in its entirety, and one or more pharmaceuticallyacceptable carriers for the treatment of heart failure disease. In someembodiments, the heart failure disease is heart failure with preservedejection fraction (HFPEF).

In another embodiment a pharmaceutical preparation is administered tothe patient, wherein said pharmaceutical composition comprises 210 mg to1260 mg of a compound having the formula:

The present disclosure also provides methods of treating a heart failuredisease by administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of any of the formulae described herein,or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, orco-crystal thereof, such that the disease is treated.

The present disclosure also provides methods of treating heart failurewith preserved ejection fraction (HFPEF) by administering to a subjectin need thereof, a therapeutically effective amount of a compound of anyof the formulae described herein, or a pharmaceutically acceptable salt,polymorph, hydrate, solvate, or co-crystal thereof, such that thedisease is treated.

The present disclosure also provides methods of reducing progression toheart failure in patients with hypertension by administering to asubject in need thereof, a therapeutically effective amount of acompound of any of the formulae described herein, or a pharmaceuticallyacceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

The present disclosure also provides compositions that enable improvedoral, controlled- or sustained-release formulations for use in thetreatment of heart failure disease. The compositions may enableformulations with a modified duration of therapeutic efficacy forreducing heart failure disease in subjects. For example, thecompositions provide therapeutically effective amounts of monomethylfumarate in subjects for at least about 8 hours, at least about 12hours, at least about 16 hours, at least about 20 hours or at leastabout 24 hours.

In some embodiments, compositions comprise a therapeutically effectiveamount of one or more prodrugs of monomethyl fumarate that are shown toprovide monomethyl fumarate plasma exposure comparable to dimethylfumarate 120 mg to 720 mg per day.

In one embodiment, one or more prodrugs of monomethyl fumarate (MMF) areadministered in combination with one or more second agents useful fortreating heart failure. In various embodiments, the second agent is adiuretic, an ace-inhibitor, a beta-blocker, an angiotensin receptorblocker, isosorbide dinitrate, hydralazine, an angiotensinreceptor-neprilysin inhibitor, an aldosterone antagonist, a PDE5inhibitor, a statin, a neprilysin inhibitor, an aldosterone inhibitor,or an antitumor necrosis factor-alpha therapy. In one embodiment, thesecond agent is a statin.

In another embodiment, a pharmaceutical composition comprises (a) acompound having the formula:

and (b) a statin and one or more pharmaceutically acceptable excipients.

In another embodiment, the pharmaceutical composition comprises acompound having the formula:

at a dose range of 210 mg to 1260 mg and a statin at a dose range of 10mg to 80 mg.

Another aspect of the disclosure provides a method of treating a heartfailure disease, in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of (a) acompound having the formula:

and either separately or together with (b) a statin. In some embodiment,the heart failure is heart failure with preserved ejection fraction.

The present disclosure also provides compositions and methods, which mayresult in decreased side effects upon administration to a subjectrelative to dimethyl fumarate. For example, gastric irritation andflushing are known side effects of oral administration of dimethylfumarate in some subjects. The compositions and methods of the presentdisclosure can be utilized in subjects that have experienced or are atrisk of developing such side effects.

The present disclosure also provides for compositions which exhibitimproved physical stability relative to dimethyl fumarate. Specifically,dimethyl fumarate is known in the art to undergo sublimation at ambientand elevated temperature conditions. The compounds of the disclosurepossess greater physical stability than dimethyl fumarate undercontrolled conditions of temperature and relative humidity.Specifically, in one embodiment, the compounds of the formulae describedherein exhibit decreased sublimation relative to dimethyl fumarate.

Further, dimethyl fumarate is also known to be a contact irritant. Inone embodiment, the compounds of the present disclosure exhibit reducedcontact irritation relative to dimethyl fumarate. For example, thecompounds of the formulae described herein exhibit reduced contactirritation relative to dimethyl fumarate.

The present disclosure also provides for compositions that exhibitdecreased food effect relative to dimethyl fumarate. The bioavailabilityof dimethyl fumarate is known in the art to be reduced when administeredwith food. Specifically, in one embodiment, the compounds of theformulae described herein exhibit decreased food effect relative todimethyl fumarate.

DETAILED DESCRIPTION

The foregoing is a summary, and thus, necessarily limited in detail. Theabove-mentioned aspects, as well as other aspects, features, andadvantages of the present technology described below in connection withvarious embodiments, with reference made to the accompanying drawings.

Definitions

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain(linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆alkyl is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl groups.Examples of alkyl include moieties having from one to six carbon atoms,such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl, or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six orfewer carbon atoms (e.g., C₁-C₆ for straight chain, C₃-C₆ for branchedchain), and in another embodiment, a straight chain or branched alkylhas four or fewer carbon atoms.

As used herein, “alkyl linker” is intended to include C₁, C₂, C₃, C₄, C₅or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups andC₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. Forexample, C₁-C₆ alkyl linker is intended to include C₁, C₂, C₃, C₄, C₅and C₆ alkyl linker groups. Examples of alkyl linker include, moietieshaving from one to six carbon atoms, such as, but not limited to, methyl(—CH₂—), ethyl (—CH₂CH₂—), n-propyl (—CH₂CH₂CH₂—), i-propyl(—CHCH₃CH₂—), n-butyl (—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl(—C(CH₃)₂CH₂—), n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl(—CHCH₃CH₂CH₂CH₂—) or n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₂—). The term“substituted alkyl linker” refers to alkyl linkers having substituentsreplacing one or more hydrogen atoms on one or more carbons of thehydrocarbon backbone. Such substituents do not alter thesp3-hybridization of the carbon atom to which they are attached andinclude those listed below for “substituted alkyl.”

“Heteroalkyl” groups are alkyl groups, as defined above, that have anoxygen, nitrogen, sulfur, or phosphorous atom replacing one or morehydrocarbon backbone carbon atoms.

As used herein, the term “cycloalkyl”, “C₃, C₄, C₅, C₆, C₇ or C₈cycloalkyl” or “C₃-C₈ cycloalkyl” is intended to include hydrocarbonrings having from three to eight carbon atoms in their ring structure.In one embodiment, a cycloalkyl group has five or six carbons in thering structure.

The term “substituted alkyl” refers to alkyl moieties havingsubstituents replacing one or more hydrogen atoms on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g.,phenylmethyl(benzyl)).

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, having from one to six, or inanother embodiment from one to four, carbon atoms in its backbonestructure. “Lower alkenyl” and “lower alkynyl” have chain lengths of,for example, two to six or two to four carbon atoms.

“Aryl” includes groups with aromaticity, including “conjugated” ormulticyclic, systems with at least one aromatic ring. Examples includephenyl, benzyl, naphthyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, having from oneto four heteroatoms in the ring structure, and may also be referred toas “aryl heterocycles” or “heteroaromatics”. As used herein, the term“heteroaryl” is intended to include a stable 5-, 6-, or 7-memberedmonocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromaticheterocyclic ring which consists of carbon atoms and one or moreheteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms,independently selected from the group consisting of nitrogen, oxygen andsulfur. The nitrogen atom may be substituted or unsubstituted (i.e., Nor NR wherein R is H or other substituents, as defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), where p=1 or 2). It is to be noted that total number of S andO atoms in the heteroaryl is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene,thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and thelike.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryland heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, orindolizine.

In the case of multicyclic aromatic rings, only one of the rings needsto be aromatic (e.g., 2,3-dihydroindole), although all of the rings maybe aromatic (e.g., quinoline). The second ring can also be fused orbridged.

The aryl or heteroaryl aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings, which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl).

As used herein, “carbocycle” or “carbocyclic ring” is intended toinclude any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. For example, a C₃-C₁₄ carbocycle is intended to include amonocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl,naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings arealso included in the definition of carbocycle, including, for example,[3.3.0] bicyclo octane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane and[2.2.2] bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro ringsare also included.

As used herein, “heterocycle” includes any ring structure (saturated orpartially unsaturated) which contains at least one ring heteroatom(e.g., N, O or S). Examples of heterocycles include, but are not limitedto, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazineand tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atomare replaced. Keto substituents are not present on aromatic moieties.Ring double bonds, as used herein, are double bonds that are formedbetween two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

As used herein, a “subject in need thereof” is a subject having a heartfailure disease. In one embodiment, a subject in need thereof has heartfailure with preserved ejection fraction (HFPEF) or is at risk ofdeveloping HFPEF. A “subject” includes a mammal. The mammal can be e.g.,any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat,cow, horse, goat, camel, sheep or a pig. In one embodiment, the mammalis a human.

As used herein, “controlled-release” means a dosage form in which therelease of the active agent is controlled or modified over a period oftime. Controlled can mean, for example, sustained, delayed orpulsed-release at a particular time. For example, controlled-release canmean that the release of the active ingredient is extended for longerthan it would be in an immediate-release dosage form, i.e., at leastover several hours.

As used herein, “immediate-release” means a dosage form in which greaterthan or equal to about 75% of the active ingredient is released withintwo hours, or, more specifically, within one hour, of administration.Immediate-release or controlled-release may also be characterized bytheir dissolution profiles.

As used herein, “pharmacokinetic parameters” describe the in vivocharacteristics of the active ingredient over time, including forexample plasma concentration of the active ingredient. As used herein,“C_(max)” means the measured concentration of the active ingredient inthe plasma at the point of maximum concentration. “T_(max)” refers tothe time at which the concentration of the active ingredient in theplasma is the highest. “AUC” is the area under the curve of a graph ofthe concentration of the active ingredient (typically plasmaconcentration) vs. time, measured from one time to another.

As used herein, “therapeutically effective amount” means an amountrequired to reduce symptoms of the disease in an individual.

Compositions

The present disclosure provides methods of treating a heart failuredisease by administering a compound herein of Formula (I), (Ia), (Ib),(II), or (III), and pharmaceutical compositions containing a compound ofFormula (I), (Ia), (Ib), (II), or (III).

The present disclosure provides, in part, methods for the treatment of aheart failure disease by administering to a subject in need thereof, atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), or (III), or a pharmaceutically acceptable salt, polymorph,hydrate, solvate, or co-crystal thereof.

In one embodiment, the heart failure disease may be heart failure withpreserved ejection fraction (HFPEF); heart failure with ejectionfraction ≥40%; diastolic heart failure; heart failure with elevatedlevels of TNF-α, IL-6, CRP, or TGF-β; hypertension with a risk ofdeveloping HFPEF; atrial fibrillation with a risk of developing HFPEF;diabetes with a risk of developing HFPEF; COPD with a risk of developingHFPEF; ischemic heart disease with a risk of developing HFPEF; obesitywith a risk of developing HFPEF; chronic heart failure; compensatedheart failure; decompensated heart failure; or other conditions known tohave a high risk of developing HFPEF. In particular, heart failuredisease is heart failure with preserved ejection fraction (HFPEF). Thepresent disclosure further provides the use of a compound of Formula(I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt,polymorph, hydrate, solvate, or co-crystal thereof, for the preparationof a medicament useful for the treatment of a heart failure disease.

In a further embodiment, the present disclosure provides methods for thetreatment of a disease or a symptom of a disease described herein byadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), or (III), or apharmaceutically acceptable salt, polymorph, hydrate, solvate, orco-crystal thereof. The present disclosure further provides the use of acompound of Formula (I), (Ia), (Ib), (II), or (III), or apharmaceutically acceptable salt, polymorph, hydrate, solvate, orco-crystal thereof, for the preparation of a medicament useful for thetreatment of a disease or a symptom of a disease described herein.

In another embodiment, the present disclosure provides a method for thetreatment of a heart failure disease by administering to a subject inneed thereof, a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, polymorph, hydrate,solvate, or co-crystal thereof:

wherein:

R₁ is unsubstituted C₁-C₆ alkyl;

L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker, substituted orunsubstituted C₃-C₁₀ carbocycle, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted heterocycle comprising one or two 5-or 6-member rings and 1-4 heteroatoms selected from N, O, and S, orsubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S; and either:

R₂ and R₃ are either:

(a) each independently, H, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstitutedC₂-C₆ alkynyl, substituted or unsubstituted C₆-C₁₀ aryl, substituted orunsubstituted C₃-C₁₀ carbocycle, substituted or unsubstitutedheterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, or substituted or unsubstitutedheteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, and S; or alternatively,

(b) form, together with the nitrogen atom to which they are attached, asubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S or asubstituted or unsubstituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

For example, the heart failure disease is HFPEF.

For example, the heart failure disease is heart failure with an ejectionfraction ≥40%.

For example, the heart failure disease is diastolic heart failure.

For example, the heart failure disease is heart failure with elevatedlevels of TNF-α, IL-6, CRP, or TGF-β.

For example, the heart failure disease is hypertension with a risk ofdeveloping HFPEF.

For example, the heart failure disease is atrial fibrillation with arisk of developing HFPEF.

For example, the heart failure disease is diabetes with a risk ofdeveloping HFPEF.

For example, the heart failure disease is COPD with a risk of developingHFPEF.

For example, the heart failure disease is ischemic heart disease with arisk of developing HFPEF.

For example, the heart failure disease is obesity with a risk ofdeveloping HFPEF.

For example, the heart failure disease is chronic heart failure.

For example, the heart failure disease is compensated heart failure.

For example, the heart failure disease is decompensated heart failure.

For example, the heart failure disease is a condition that has a highrisk of developing HFPEF.

For example, the compound of Formula (I) is a compound listed in Table1.

For example, in the compound of Formula (I), R₁ is methyl.

For example, in the compound of Formula (I), R₁ is ethyl.

For example, in the compound of Formula (I), L_(a) is substituted orunsubstituted C₁-C₆ alkyl linker.

For example, in the compound of Formula (I), L_(a) is substituted orunsubstituted C₁-C₃ alkyl linker.

For example, in the compound of Formula (I), L_(a) is substituted orunsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is methyl substitutedor unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is di-methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is methyl ordi-methyl substituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is unsubstituted C₂alkyl linker.

For example, in the compound of Formula (I), R₂ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (I), R₂ isC(O)OR_(a)-substituted C₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (I), R₂ isS(O)(O)R_(b)-substituted C₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (I), R₃ is H.

For example, in the compound of Formula (I), R₃ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (I), R₃ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl,piperazinyl, or morpholinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted piperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpiperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a halogen substitutedpiperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a 4-halogensubstituted piperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedmorpholinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpyrrolidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5 or 6-member rings and1-4 heteroatoms selected from N, O, and S.

For example, in the compound of Formula (I), R₂ is substituted orunsubstituted C₆-C₁₀ aryl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₆-C₁₀aryl.

For example, in the compound of Formula (I), R₂ is unsubstituted phenyl.

For example, in the compound of Formula (I), R₂ is unsubstituted benzyl.

In another embodiment, the present disclosure provides a method for thetreatment of a heart failure disease by administering to a subject inneed thereof a therapeutically effective amount of a compound of Formula(Ia), or a pharmaceutically acceptable salt, polymorph, hydrate,solvate, or co-crystal thereof:

wherein:

R₁ is unsubstituted C₁-C₆ alkyl;

L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker, substituted orunsubstituted C₃-C₁₀ carbocycle, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted heterocycle comprising one or two 5-or 6-member rings and 1-4 heteroatoms selected from N, O, and S, orsubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S; and

R₂ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₆-C₁₀ aryl, substituted or unsubstitutedC₃-C₁₀ carbocycle, substituted or unsubstituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O,and S, or substituted or unsubstituted heteroaryl comprising one or two5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S.

For example, the heart failure disease is HFPEF.

For example, the heart failure disease is heart failure with an ejectionfraction ≥40%.

For example, the heart failure disease is diastolic heart failure.

For example, the heart failure is heart failure with elevated levels ofTNF-α, IL-6, CRP, or TGF-β.

For example, the heart failure disease is hypertension with a risk ofdeveloping HFPEF.

For example, the heart failure disease is atrial fibrillation with arisk of developing HFPEF.

For example, the heart failure disease is diabetes with a risk ofdeveloping HFPEF.

For example, the heart failure disease is COPD with a risk of developingHFPEF.

For example, the heart failure disease is ischemic heart disease with arisk of developing HFPEF

For example, the heart failure disease is obesity with a risk ofdeveloping HFPEF.

For example, the heart failure disease is chronic heart failure.

For example, the heart failure disease is compensated heart failure.

For example, the heart failure disease is decompensated heart failure.

For example, the heart failure disease is a condition that has a highrisk of developing HFPEF.

For example, in the compound of Formula (Ia), R₁ is methyl.

For example, in the compound of Formula (Ia), R₁ is ethyl.

For example, in the compound of Formula (Ia), L_(a) is substituted orunsubstituted C₁-C₆ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is substituted orunsubstituted C₁-C₃ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is substituted orunsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is di-methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is methyl ordi-methyl substituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is unsubstituted C₂alkyl linker.

For example, in the compound of Formula (Ia), R₂ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (Ia), R₂ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ia), R₂ is methyl.

For example, in the compound of Formula (Ia), R₂ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (Ia), R₂ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (Ia), R₂ isC(O)OR_(a)-substituted C₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (Ia), R₂ isS(O)(O)R_(b)-substituted C₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

In another embodiment, the present disclosure provides a method for thetreatment of a heart failure disease by administering to a subject inneed thereof a therapeutically effective amount of a compound of Formula(Ib), or a pharmaceutically acceptable polymorph, hydrate, solvate, orco-crystal thereof:

A⁻ is a pharmaceutically acceptable anion;

R₁ is unsubstituted C₁-C₆ alkyl;

L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker, substituted orunsubstituted C₃-C₁₀ carbocycle, substituted or unsubstituted C₆-C₁₀aryl, substituted or unsubstituted heterocycle comprising one or two 5-or 6-member rings and 1-4 heteroatoms selected from N, O, and S, orsubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S;

R₃′ is substituted or unsubstituted C₁-C₆ alkyl; and either:

(a) R₂ and R₃ are each, independently, H, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₆-C₁₀ aryl,substituted or unsubstituted C₃-C₁₀ carbocycle, substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S; or alternatively,

(b) R₂ and R₃, together with the nitrogen atom to which they areattached, form a substituted or unsubstituted heteroaryl comprising oneor two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, andS, or a substituted or unsubstituted heterocycle comprising one or two5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S.

For example, the heart failure disease is HFPEF.

For example, the heart failure disease is heart failure with an ejectionfraction ≥40%.

For example, the heart failure disease is diastolic heart failure.

For example, the heart failure disease is heart failure with elevatedlevels of TNF-α, IL-6, CRP, or TGF-β.

For example, the heart failure disease is hypertension with a risk ofdeveloping HFPEF.

For example, the heart failure disease is atrial fibrillation with arisk of developing HFPEF.

For example, the heart failure disease is diabetes with a risk ofdeveloping HFPEF.

For example, the heart failure disease is COPD with a risk of developingHFPEF.

For example, the heart failure disease is ischemic heart disease with arisk of developing HFPEF.

For example, the heart failure disease is obesity with a risk ofdeveloping HFPEF.

For example, the heart failure disease is chronic heart failure.

For example, the heart failure disease is compensated heart failure.

For example, the heart failure disease is decompensated heart failure.

For example, the heart failure disease is a condition that has a highrisk of developing HFPEF.

For example, in the compound of Formula (Ib), R₁ is methyl.

For example, in the compound of Formula (Ib), R₁ is ethyl.

For example, in the compound of Formula (Ib), L_(a) is substituted orunsubstituted C₁-C₆ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is substituted orunsubstituted C₁-C₃ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is substituted orunsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is di-methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is methyl ordi-methyl substituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is unsubstituted C₂alkyl linker.

For example, in the compound of Formula (Ib), R₂ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (Ib), R₂ isC(O)OR_(a)-substituted C₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₂ isS(O)(O)R_(b)-substituted C₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₃ is H.

For example, in the compound of Formula (Ib), R₃ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₃ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl,piperazinyl, or morpholinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted piperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpiperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a halogen substitutedpiperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a 4-halogensubstituted piperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedmorpholinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpyrrolidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S.

For example, in the compound of Formula (Ib), R₂ is substituted orunsubstituted C₆-C₁₀ aryl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₆-C₁₀aryl.

For example, in the compound of Formula (Ib), R₂ is unsubstitutedphenyl.

For example, in the compound of Formula (Ib), R₂ is unsubstitutedbenzyl.

For example, in the compound of Formula (Ib), R₃′ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ib), R₃′ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (Ib), R₃′ is methyl.

In one embodiment, the present disclosure a method for the treatment ofa heart failure disease by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (II), or apharmaceutically acceptable salt, polymorph, hydrate, solvate, orco-crystal thereof:

wherein:

R₁ is unsubstituted C₁-C₆ alkyl;

R₄ and R₅ are each, independently, H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₆-C₁₀ aryl,substituted or unsubstituted C₃-C₁₀ carbocycle, substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S;

R₆, R₇, R₈ and R₉ are each, independently, H, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl,substituted or unsubstituted C₂-C₆ alkynyl or C(O)OR_(a); and

R_(a) is H or substituted or unsubstituted C₁-C₆ alkyl.

For example, the heart failure disease is HFPEF.

For example, the heart failure disease is heart failure with an ejectionfraction ≥40%.

For example, the heart failure disease is diastolic heart failure.

For example, the heart failure disease is heart failure with elevatedlevels of TNF-α, IL-6, CRP, or TGF-β.

For example, the heart failure disease is hypertension with a risk ofdeveloping HFPEF.

For example, the heart failure disease is atrial fibrillation with arisk of developing HFPEF.

For example, the heart failure disease is diabetes with a risk ofdeveloping HFPEF.

For example, the heart failure disease is COPD with a risk of developingHFPEF.

For example, the heart failure disease is ischemic heart disease with arisk of developing HFPEF.

For example, the heart failure disease is obesity with a risk ofdeveloping HFPEF.

For example, the heart failure disease is chronic heart failure.

For example, the heart failure disease is compensated heart failure.

For example, the heart failure disease is decompensated heart failure.

For example, the heart failure disease is a condition that has a highrisk of developing HFPEF.

For example, in the compound of Formula (II), R₁ is methyl.

For example, in the compound of Formula (II), R₁ is ethyl.

For example, in the compound of Formula (II), R₄ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (II), R₄ isC(O)OR_(a)-substituted C₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (II), R₄ isS(O)(O)R_(b)-substituted C₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (II), R₅ is H.

For example, in the compound of Formula (II), R₅ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (II), R₅ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (II), R₄ is substituted orunsubstituted C₆-C₁₀ aryl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₆-C₁₀aryl.

For example, in the compound of Formula (II), R₄ is unsubstitutedphenyl.

For example, in the compound of Formula (II), R₄ is unsubstitutedbenzyl.

For example, in the compound of Formula (II), R₆, R₇, R₈ and R₉ are eachH.

For example, in the compound of Formula (II), R₆ is substituted orunsubstituted C₁-C₆ alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (II), R₆ is unsubstituted C₁-C₆alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (II), R₈ is substituted orunsubstituted C₁-C₆ alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (II), R₈ is unsubstituted C₁-C₆alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (II), R₆ and R₈ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₇ and R₉are each H.

For example, in the compound of Formula (II), R₆ and R₈ are each,independently, unsubstituted C₁-C₆ alkyl and R₇ and R₉ are each H.

For example, in the compound of Formula (II), R₆ and R₇ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₈ and R₉are each H.

For example, in the compound of Formula (II), R₆ and R₇ are each,independently, unsubstituted C₁-C₆ alkyl and R₈ and R₉ are each H.

For example, in the compound of Formula (II), R₈ and R₉ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₆ and R₇are each H.

For example, in the compound of Formula (II), R₈ and R₉ are each,independently, unsubstituted C₁-C₆ alkyl and R₆ and R₇ are each H.

In one embodiment, the present disclosure provides a method for thetreatment of a heart failure disease by administering to a subject inneed thereof a therapeutically effective amount of a compound of Formula(III), or a pharmaceutically acceptable salt, polymorph, hydrate,solvate, or co-crystal thereof:

wherein:

R₁ is unsubstituted C₁-C₆ alkyl;

is selected from the group consisting of:

X is N, O, S, or SO₂;

Z is C or N;

m is 0, 1, 2, or 3;

n is 1 or 2;

w is 0, 1, 2, or 3;

t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R₆, R₇, R₈ and R₉ are each, independently, H, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl,substituted or unsubstituted C₂-C₆ alkynyl or C(O)OR_(a); and

R_(a) is H or substituted or unsubstituted C₁-C₆ alkyl; and either:

(a) each R₁₀ is, independently, H, halogen, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₃-C₁₀carbocycle, substituted or unsubstituted heterocycle comprising one ortwo 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S,or substituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S; oralternatively

(b) two R₁₀'s attached to the same carbon atom, together with the carbonatom to which they are attached, form a carbonyl, substituted orunsubstituted C₃-C₁₀ carbocycle, substituted or unsubstitutedheterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, and S, or substituted or unsubstitutedheteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, and S; or alternatively

(c) two R₁₀'s attached to different atoms, together with the atoms towhich they are attached, form a substituted or unsubstituted C₃-C₁₀carbocycle, substituted or unsubstituted heterocycle comprising one ortwo 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S,or substituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.

For example, the heart failure disease is HFPEF.

For example, the heart failure disease is heart failure with an ejectionfraction ≥40%.

For example, the heart failure disease is diastolic heart failure.

For example, the heart failure is heart failure with elevated levels ofTNF-α, IL-6, CRP, or TGF-β.

For example, the heart failure disease is hypertension with a risk ofdeveloping HFPEF.

For example, the heart failure disease is atrial fibrillation with arisk of developing HFPEF.

For example, the heart failure disease is diabetes with a risk ofdeveloping HFPEF.

For example, the heart failure disease is COPD with a risk of developingHFPEF.

For example, the heart failure disease is ischemic heart disease with arisk of developing HFPEF.

For example, the heart failure disease is obesity with a risk ofdeveloping HFPEF.

For example, the heart failure disease is chronic heart failure.

For example, the heart failure disease is compensated heart failure.

For example, the heart failure disease is decompensated heart failure.

For example, the heart failure disease is a condition that has a highrisk of developing HFPEF.

For example, in the compound of Formula (III), R₁ is methyl.

For example, in the compound of Formula (III), R₁ is ethyl.

For example, in the compound of Formula (III),

is

For example, in the compound of Formula (III),

is

For example, in the compound of Formula (III),

is

For example, in the compound of Formula (III),

is

For example, in the compound of Formula (III), R₆ is substituted orunsubstituted C₁-C₆ alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (III), R₆ is unsubstituted C₁-C₆alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (III), R₈ is substituted orunsubstituted C₁-C₆ alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (III), R₈ is unsubstituted C₁-C₆alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (III), R₆ and R₈ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₇ and R₉are each H.

For example, in the compound of Formula (III), R₆ and R₈ are each,independently, unsubstituted C₁-C₆ alkyl and R₇ and R₉ are each H.

For example, in the compound of Formula (III), R₆ and R₇ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₈ and R₉are each H.

For example, in the compound of Formula (III), R₆ and R₇ are each,independently, unsubstituted C₁-C₆ alkyl and R₈ and R₉ are each H.

For example, in the compound of Formula (III), R₈ and R₉ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₆ and R₇are each H.

For example, in the compound of Formula (III), R₈ and R₉ are each,independently, unsubstituted C₁-C₆ alkyl and R₆ and R₇ are each H.

For example, the compound is a compound listed in Table 1

Representative compounds includes compounds listed in Table 1.

TABLE 1 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Dosage and Administration

The present disclosure also provides pharmaceutical compositionscomprising one or more compounds of Formula (I), (Ia), (Ib), (II), or(III) and one or more pharmaceutically acceptable carriers for use intherapy of a heart failure disease, including heart failure withpreserved ejection fraction.

In one embodiment, the pharmaceutical composition is a controlledrelease composition comprising a compound of Formula (I), (Ia), (Ib),(II), or (III) and one or more pharmaceutically acceptable carriers,wherein the controlled release composition provides a therapeuticallyeffective amount of monomethyl fumarate to a subject. In anotherembodiment, the pharmaceutical composition is a controlled releasecomposition comprising a compound of Formula (I), (Ia), (Ib), (II), or(III) and one or more pharmaceutically acceptable carriers, wherein thecontrolled release composition provides a therapeutically effectiveamount of monomethyl fumarate to a subject for at least about 8 hours toat least about 24 hours.

In another embodiment, the pharmaceutical composition is a controlledrelease composition comprising a compound of Formula (I), (Ia), (Ib),(II), or (III) and one or more pharmaceutically acceptable carriers,wherein the controlled release composition provides a therapeuticallyeffective amount of monomethyl fumarate to a subject for at least about8 hours, at least about 10 hours, at least about 12 hours, at leastabout 13 hours, at least about 14 hours, at least about 15 hours, atleast about 16 hours, at least about 17 hours, at least about 18 hours,at least about 19 hours, at least about 20 hours, at least about 21hours, at least about 22 hours, at least about 23 hours or at leastabout 24 hours or longer. For example, at least about 18 hours. Forexample, at least about 12 hours. For example, greater than 12 hours.For example, at least about 16 hours. For example, at least about 20hours. For example, at least about 24 hours.

In another embodiment, a compound of Formula (I), (Ia), (Ib), (II), or(III) is efficiently converted to the active species, i.e., monomethylfumarate, upon oral administration. For example, about 50 mole percent,about 55 mole percent, about 60 mole percent, about 65 mole percent,about 70 mole percent, about 75 mole percent, about 80 mole percent,about 85 mole percent, about 90 mole percent, or greater than 90 molepercent of the total dose of a compound of Formula (I), (Ia), (Ib),(II), or (III) administered is converted to monomethyl fumarate uponoral administration. In another embodiment, a compound of Formula (I),(Ia), (Ib), (II), or (III) is converted to the active species, i.e.,monomethyl fumarate, upon oral administration more efficiently thandimethyl fumarate. In another embodiment, a compound of Formula (I),(Ia), (Ib), (II), or (III) is converted to the active species, i.e.,monomethyl fumarate, upon oral administration more efficiently than oneor more of the compounds described in U.S. Pat. No. 8,148,414, thedisclosure of which is incorporated by reference in its entirety. Forexample, a compound of Formula (I), (Ia), (Ib), (II), or (III) isessentially completely converted to the active species, i.e., monomethylfumarate, upon oral administration.

In another embodiment, any one of Compounds 1-20, as shown in Table 1,is efficiently converted to the active species, i.e., monomethylfumarate, upon oral administration. For example, about 50 percent, about55 percent, about 60 percent, about 65 percent, about 70 percent, about75 percent, about 80 percent, about 85 percent, about 90 percent, orgreater than 90 percent of the total dose of any one of Compounds 1-20of Table 1 administered is converted to monomethyl fumarate upon oraladministration. In another embodiment, any one of Compounds 1-20 ofTable 1 is converted to the active species, i.e., monomethyl fumarate,upon oral administration more efficiently than dimethyl fumarate. Inanother embodiment, any one of Compounds 1-20 of Table 1 is converted tothe active species, i.e., monomethyl fumarate, upon oral administrationmore efficiently than one or more of the compounds described in U.S.Pat. No. 8,148,414, the disclosure of which is herein incorporated byreference in its entirety. For example, any one of Compounds 1-20 ofTable 1 is completely converted to the active species, i.e., monomethylfumarate, upon oral administration.

For a drug to achieve its therapeutic effect, it is necessary tomaintain the required level of blood or plasma concentration. Manydrugs, including dimethyl fumarate, must be administered multiple timesa day to maintain the required concentration. Furthermore, even withmultiple administrations of such a drug per day, the blood or plasmaconcentrations of the active ingredient may still vary with time, i.e.,at certain time points between administrations there are higherconcentrations of the active ingredient than at other times. Thus, atcertain time points of a 24-hour period, a patient may receivetherapeutically effective amounts of the active ingredient, while atother time points the concentration of the active ingredient in theblood may fall below therapeutic levels. Additional problems with suchdrugs include that multiple dosing a day often adversely affects patientcompliance with the treatment. Therefore, it is desirable to have a drugdosage form wherein the active ingredient is delivered in such acontrolled manner that a constant or substantially constant level ofblood or plasma concentration of the active ingredient can be achievedby one or at most two dosing per day. Accordingly, the presentdisclosure provides controlled-release formulations as described below.In general, such formulations are known to those skilled in the art orare available using conventional methods.

The controlled-release formulations provided herein provide desirableproperties and advantages. For example, the formulations can beadministered once daily, which is particularly desirable for thesubjects described herein. The formulation can provide many therapeuticbenefits that are not achieved with corresponding shorter acting orimmediate-release preparations. For example, the formulation canmaintain lower, more steady plasma peak values, for example, C_(max), soas to reduce the incidence and severity of possible side effects.

Sustained-release dosage forms release their active ingredient into thegastro-intestinal tract of a patient over a sustained period of timefollowing administration of the dosage form to the patient. Particulardosage forms include: (a) those in which the active ingredient isembedded in a matrix from which it is released by diffusion or erosion;(b) those in which the active ingredient is present in a core which iscoated with a release rate-controlling membrane; (c) those in which theactive ingredient is present in a core provided with an outer coatingimpermeable to the active ingredient, the outer coating having anaperture (which may be drilled) for release of the active ingredient;(d) those in which the active ingredient is released through asemi-permeable membrane, allowing the drug to diffuse across themembrane or through liquid filled pores within the membrane; and (e)those in which the active ingredient is present as an ion exchangecomplex.

It will be apparent to those skilled in the art that some of the abovemeans of achieving sustained-release may be combined, for example amatrix containing the active compound may be formed into amultiparticulate and/or coated with an impermeable coating provided withan aperture.

Pulsed-release formulations release the active compound after asustained period of time following administration of the dosage form tothe patient. The release may then be in the form of immediate- orsustained-release. This delay may be achieved by releasing the drug atparticular points in the gastro-intestinal tract or by releasing drugafter a pre-determined time. Pulsed-release formulations may be in theform of tablets or multiparticulates or a combination of both.Particular dosage forms include: (a) osmotic potential triggered release(see U.S. Pat. No. 3,952,741); (b) compression coated two layer tablets(see U.S. Pat. No. 5,464,633); (c) capsules containing an erodible plug(see U.S. Pat. No. 5,474,784); (d) sigmoidal releasing pellets (referredto in U.S. Pat. No. 5,112,621); and (e) formulations coated with orcontaining pH-dependent polymers including shellac, phthalatederivatives, polyacrylic acid derivatives, and crotonic acid copolymers.

Dual release formulations can combine the active ingredient in immediaterelease form with additional active ingredient in controlled-releaseform. For example, a bilayer tablet can be formed with one layercontaining immediate release active ingredient and the other layercontaining the active ingredient embedded in a matrix from which it isreleased by diffusion or erosion. Alternatively, one or more immediaterelease beads can be combined with one or more beads which are coatedwith a release rate-controlling membrane in a capsule to give a dualrelease formulation. Sustained release formulations in which the activeingredient is present in a core provided with an outer coatingimpermeable to the active ingredient, the outer coating having anaperture (which may be drilled) for release of the active ingredient,can be coated with drug in immediate release form to give a dual releaseformulation. Dual release formulations can also combine drug inimmediate release form with additional drug in pulsed release form. Forexample, a capsule containing an erodible plug could liberate druginitially and, after a predetermined period of time, release additionaldrug in immediate- or sustained-release form.

In some embodiments, the dosage forms to be used can be provided ascontrolled-release with respect to one or more active ingredientstherein using, for example, hydroxypropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the pharmaceutical compositions of the disclosure.Thus, single unit dosage forms suitable for oral administration, such astablets, capsules, gelcaps, and caplets that are adapted forcontrolled-release are encompassed by the present disclosure.

Most controlled-release formulations are designed to initially releasean amount of drug that promptly produces the desired therapeutic effectand gradually and continually release additional amounts of drug tomaintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.

Controlled-release of an active ingredient can be stimulated by variousinducers, for example pH, temperature, enzymes, concentration, or otherphysiological conditions or compounds.

Powdered and granular formulations of a pharmaceutical preparation ofthe disclosure may be prepared using known methods. Such formulationsmay be administered directly to a subject, used, for example, to formtablets, to fill capsules, or to prepare an aqueous or oily suspensionor solution by addition of an aqueous or oily vehicle thereto. Each ofthese formulations may further comprise one or more of a dispersingagent, wetting agent, suspending agent, and a preservative. Additionalexcipients, such as fillers, sweeteners, flavoring, or coloring agents,may also be included in these formulations.

A formulation of a pharmaceutical composition of the disclosure suitablefor oral administration may be prepared or packaged in the form of adiscrete solid dose unit including, but not limited to, a tablet, a hardor soft capsule, a cachet, a troche, or a lozenge, each containing apredetermined amount of the active ingredient. In one embodiment, aformulation of a pharmaceutical composition of the disclosure suitablefor oral administration is coated with an enteric coating.

A tablet comprising the active ingredient may, for example, be made bycompressing or molding the active ingredient, optionally with one ormore additional ingredients. Compressed tablets may be prepared bycompressing, in a suitable device, the active ingredient in a freeflowing form such as a powder or granular preparation, optionally mixedwith one or more of a binder, a lubricant, an excipient, asurface-active agent, and a dispersing agent. Molded tablets may be madeby molding, in a suitable device, a mixture of the active ingredient, apharmaceutically acceptable carrier, and at least sufficient liquid tomoisten the mixture. Pharmaceutically acceptable excipients used in themanufacture of tablets include, but are not limited to, inert diluents,granulating and disintegrating agents, binding agents, and lubricatingagents. Known dispersing agents include, but are not limited to, potatostarch and sodium starch glycollate. Known surface-active agentsinclude, but are not limited to, sodium lauryl sulphate and poloxamers.Known diluents include, but are not limited to, calcium carbonate,sodium carbonate, lactose, microcrystalline cellulose, calciumphosphate, calcium hydrogen phosphate, and sodium phosphate. Knowngranulating and disintegrating agents include, but are not limited to,corn starch and alginic acid. Known binding agents include, but are notlimited to, gelatin, acacia, pre-gelatinized maize starch,polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Knownlubricating agents include, but are not limited to, magnesium stearate,stearic acid, silica, and talc.

Tablets may be non-coated or they may be coated using known methods toachieve delayed disintegration in the gastrointestinal tract of asubject, thereby providing sustained release and absorption of theactive ingredient. By way of example, a material such as glycerylmonostearate or glyceryl distearate may be used to coat tablets. Furtherby way of example, tablets may be coated using methods described in U.S.Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, the disclosure of whichare each herein incorporated by reference in their entireties, to formosmotically-controlled release tablets, optionally, with laser drilling.Tablets may further comprise a sweetener, a flavoring agent, a coloringagent, a preservative, or some combination of these in order to providefor pharmaceutically elegant and palatable formulations.

Hard capsules comprising the active ingredient may be made using aphysiologically degradable composition, such as gelatin or HPMC. Suchhard capsules comprise the active ingredient, and may further compriseadditional ingredients including, for example, an inert solid diluentsuch as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made usinga physiologically degradable composition, such as gelatin. Such softcapsules comprise the active ingredient, which may be mixed with wateror an oil medium such as peanut oil, liquid paraffin, or olive oil.

The dose will be adjusted to the individual requirements in eachparticular case. That dosage may vary within wide limits depending uponnumerous factors such as the severity of the disease to be treated, theage and general health condition of the patient, other medicaments withwhich the patient is being treated, the route and form ofadministration, and the preferences and experience of the medicalpractitioner involved. For oral administration. therapeuticallyeffective amount of one or more prodrug of monomethyl fumarate that isshown to provide MMF plasma exposure comparable to 120 mg to 720 mg perday of dimethyl fumarate (DMF) as a monotherapy and/or in combinationtherapy. In one embodiment, daily dose comprises 210 mg to 1260 mg ofthe compound having the formula:

In another embodiment, the daily dose would be 420 mg BID, with theupper limit being 420 mg TID of the compound having the formula

One of ordinary skill in treating diseases described herein will beable, without undue experimentation and in reliance on personalknowledge, experience and the disclosures of this application, toascertain a therapeutically effective amount of the compounds of thepresent invention for a given disease and patient.

According to the present disclosure, administration of one or moreprodrug of monomethyl fumarate may also be carried out in thecombination with administration of one or more preparations of a secondagent useful for treating heart failure, such as but not limited todiuretics, ace-inhibitors, beta-blockers, angiotensin receptor blockers,isosorbide dinitrate, hydralazine , angiotensin receptor-neprilysininhibitors, aldosterone antagonists, a PDE5 inhibitor, a statin, aneprilysin inhibitor, an aldosterone inhibitor, or an antitumor necrosisfactor-alpha therapy. In one embodiment, the second agent is a statin,for example atorvastatin, fluvastatin, lovastatin, pravastatin,rosuvastatin, or simvastatin. For this purpose, the preparationsadministered may comprise a combination of the active ingredients in theknown dosages or amounts, respectively. Likewise, the combinationtherapy may comprise the parallel administration of separatepreparations, by the same or different routes. Optionally, the dosage ofthe active ingredient comprised in addition to the dose of the fumaricacid derivative administered in accordance with the present disclosuremay be reduced advantageously.

In one embodiment, combination relates to (a) a compound having theformula:

and (b) a statin for treatment of heart failure disease, including heartfailure with preserved ejection fraction. In some embodiments, apharmaceutical composition is provided comprising (a) a compound havingthe formula

and (b) a statin. In one embodiment, a compound having the fort

is administered at a dose range of 210 mg to 1260 mg and a statin isgiven at a dose range of 10 mg to 80 mg for treatment of heart failuredisease, including heart failure with preserved ejection fraction. Insome embodiments, the statin is selected from group consisting ofatorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, andsimvastatin.

The prodrugs of monomethyl fumarate (MMF) to be used according to thepresent disclosure are prepared by processes known in the art (see, forexample U.S. Pat. No. 8,669,281, the disclosure of which is hereinincorporated by reference in its entirety).

PROPHETIC EXAMPLE 1

The following prophetic example serves to provide approximate dosagelevels of prodrugs of monomethyl fumarate to achieve the intendedeffect, for example treatment of heart failure with preserved ejectionfraction (HFPEF). Based on the literature, a few assumptions about thedosage can be made, as will be described in further detail below.

The full mechanism of fumaric acid esters such as dimethyl fumarate(DMF) and its primary metabolite, monomethyl fumarate (MMF), is notcompletely understood, but their beneficial effects appear to bemediated, at least in part, through the activation of the NRF2antioxidant response pathway, which further increases expression of ARE,which increases expression of detoxifying enzymes and antioxidantproteins.

NRF2 deficiency, demonstrated by NRF2 knockout in murine models, resultsin an earlier onset of cardiac dysfunction induced by pressure andvolume overload (Li et al Arterioscler Thromb Vasc Biol. 2009, 29(11),1843-50). Certain NRF2 activators such as sulforaphane, curcumin,carbobenzoxy-Leu-Leu (MG132), resveratrol, garlic organosulfurcompounds, allicin, 4-hydroxynonenal (4-HNE), α-lipoic acid, hydrogensulfate, and 17α-estradiol have been used as therapeutic targets toreduce cardiac remodeling, but prodrugs of monomethyl fumarate have notbeen used yet to reduce cardiac remodeling (Zhou et al; J Appl Physiol.2015, 119(8), 944-951).

Fumarates are cardioprotective in acute situations via activation of theNRF2 pathway in acute ischemia due to myocardial infarction (Ashrafianet. al ; Cell Metab. 2012, 15(3), 361-71). However, Ashrafian et. alclaims that fumarates are harmful in chronic situations, including heartfailure. Prodrugs of monomethyl fumarate are herein proposed to achievethe intended effect, for example, treatment of chronic heart failurewith preserved ejection fraction (HFPEF).

Dimethyl Fumarate has been tested for multiple sclerosis and psoriasisat multiple dosages in the past, including 120 mg, 240 mg, daily, BID,and TID. The side effect profile was similar regardless of which dosagewas used. In order to determine dosage of a prodrug of monomethylfumarate, a dose escalation study may be conducted to find a comparabledosage of the MMF prodrug to DMF's 240 mg dose, by comparing plasmalevels of MMF. For example, one MMF prodrug known as ALKS 8700, acompound having formula:

has been tested in such a way to determine that 420 mg of ALKS 8700 is acomparable dose of 240 mg DMF (Tecfidera) by comparing plasma levels ofMMF. (Hunt et al. Safety, Tolerability, and Pharmacokinetics of ALKS8700, a Novel Oral Therapy for Relapsing-Remitting Multiple Sclerosis,in Healthy Subjects). Various dosages of an MMF prodrug will be testedin HFPEF patients so that the dosage that is comparable to a DMF dosageof 120 mg, 240 mg, daily, BID, and TID may be determined. Using ALKS8700 as one such MMF, such dosage is calculated to be 210 mg, 420 mg,daily, BID, TID in patients with HFPEF.

Furthermore, pro-inflammatory cytokines IL-6 and TNF-α are raised inHFPEF, which may lead to increase activity of VCAM, E-Selection, andNADPH oxidase, which increase ROS in coronary microvasculatureendothelial cells, leading to the hallmarks of HFPEF: ventricularstiffness, impaired relaxation, and cardiac dysfunction. The prodrugs ofmonomethyl fumarate may reduce damage of ROS in heart failure bymultiple pathways including increasing the NRF2/ARE pathway, andpossibly by reducing NF-kB, which reduces IL-6 and TNF-α.

LCZ696, a combined angiotensin receptor neprilysin inhibitor (ARNI) thathas recently shown to reduce mortality in HFREF but not in HFPEFpatients. LCZ696 inhibits natriuretic peptide breakdown and enhancescGMP activation, and in HFPEF was associated with incremental reductionsin circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP)levels when compared to treatment with the ARB valsartan, alone.However, these reductions were incremental, and it is yet to be seenwhether LCZ696 or other angiotensin receptor-neprilysin inhibitors willlead to any significant mortality or clinical benefit in HFPEF patients.Furthermore, the comparison with ARB valsartan alone, is flawed in thatARB valsartan is used in the treatment of HFREF but not in HFPEF.

The patients' baseline TNF-alpha, IL-6, NT-proBNP will be measured atthe start of the trial and compared to levels at various intervals(weeks to months to years) to determine the ideal dosage based onreductions in TNF-alpha, IL-6, and/or NT-proBNP. Such a dosage will thenbe tested in a larger group of HFPEF patients to measure changes inmorbidity and mortality. Thus an ideal dosage of prodrug of MMF fortreating HFPEF will be comparable to a dosage of 120 mg or 240 mg,daily, BID, or TID of DMF (Tecfidera), by measuring MMF concentrationsin the blood. In the case of ALKS 8700, this dosage range is 210 mg to420 mg, daily, BID, or TID, for a range of 210 mg to 1260 mg during anygiven day.

PROPHETIC EXAMPLE 2

Based on the above prophetic example, an exemplary, non-limitingembodiment is described in detail below. As described herein, a user mayinclude a male or female between the ages of 50 to 100 with ejectionfraction of greater than 40%, and more likely to be a female with adocumented history of high blood pressure, diabetes, and/or COPD, withat least one episode of fluid overload, or who has HFPEF or is at riskof developing (HFPEF).

The most common disease leading to HFPEF is systolic hypertension, whichis present in more than 85% of patients. Patients with HFPEF have normalleft ventricular (LV) end-diastolic volume and normal (or near-normal)EF and stroke volume and commonly exhibit concentric remodeling ofeither the LV chamber and/or cardiomyocytes.

Patients with HFPEF have a devastating 5-year mortality rate(approaching 60%), costly morbidity (6-month hospitalization rate of50%), and debilitating symptoms (maximum myocardial oxygen consumption[MVo₂] averaging 14 mL/g/min).

More than half of heart failure patients have heart failure withpreserved ejection fraction (HFPEF). Morbidity and mortality of HFPEFare similar to HFREF; however, medications proven effective in HFREFhave not been found to be effective in HFPEF. At present there are noapproved treatments to reduce mortality in HFPEF. In HFREF, medicationssuch as beta-blockers, ace-inhibitors, angiotensin receptor blockers,isosorbide dinitrate, hydralazine, aldosterone inhibitors, andangiotensin receptor neprilysin inhibitors have been shown to providebenefit. However, these medications have not shown to be beneficial inpatients with HFPEF, and are not approved therapies for HFPEF.

PROPHETIC EXAMPLE 3

The following prophetic example serves to provide a combination therapyfor patients with HFPEF, which includes a prodrug of MMF with a statin.To date there has been no prospective studies of statins in patientswith HFPEF. However, statins have pleotropic effects, in which they havebeen shown to be beneficial to non-HFPEF patients beyond what waspredicted based on their ability to reduce cholesterol, likely throughanti-inflammatory pathways. By combining a statin with a prodrug of MMF,a synergistic effect to reduce the ROS associated with HFPEF isexpected, which in turn will reduce stiffness in HFPEF and also reducebiomarkers such as IL-6, TNF-alpha, or NT-proBNP, and ultimately improvesurvival in HFPEF patients. In one such example, a dose range between210 mg to 1260 mg of MMF (ALKS 8700) is given to a patient with a statindosage between 10 mg to 80 mg.

As used in the description and claims, the singular form “a”, “an” and“the” include both singular and plural references unless the contextclearly dictates otherwise. For example, the term “prodrug” may include,and is contemplated to include, a plurality of prodrugs. At times, theclaims and disclosure may include terms such as “a plurality,” “one ormore,” or “at least one;” however, the absence of such terms is notintended to mean, and should not be interpreted to mean, that aplurality is not conceived.

The term “about” or “approximately,” when used before a numericaldesignation or range (e.g., to define a length or pressure), indicatesapproximations which may vary by (+) or (−) 5%, 1% or 0.1%. Allnumerical ranges provided herein are inclusive of the stated start andend numbers. The term “substantially” indicates mostly (i.e., greaterthan 50%) or essentially all of a method, substance, or composition.

As used herein, the term “comprising” or “comprises” is intended to meanthat the methods and compositions include the recited elements, and mayadditionally include any other elements. “Consisting essentially of”shall mean that the methods and compositions include the recitedelements and exclude other elements of essential significance to thecombination for the stated purpose. Thus, a method or compositionconsisting essentially of the elements as defined herein would notexclude other materials, features, or steps that do not materiallyaffect the basic and novel characteristic(s) of the claimed disclosure.“Consisting of” shall mean that the methods and compositions include therecited elements and exclude anything more than a trivial orinconsequential element or step. Embodiments defined by each of thesetransitional terms are within the scope of this disclosure.

The terms “optionally” as used herein means that a subsequentlydescribed event or circumstance may but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. Other embodiments may be utilized andderived therefrom, such that structural and logical substitutions andchanges may be made without departing from the scope of this disclosure.Such embodiments of the inventive subject matter may be referred toherein individually or collectively by the term “invention” merely forconvenience and without intending to voluntarily limit the scope of thisapplication to any single invention or inventive concept, if more thanone is in fact disclosed. Thus, although specific embodiments have beenillustrated and described herein, any arrangement calculated to achievethe same purpose may be substituted for the specific embodiments shown.This disclosure is intended to cover any and all adaptations orvariations of various embodiments. Combinations of the aboveembodiments, and other embodiments not specifically described herein,will be apparent to those of skill in the art upon reviewing the abovedescription.

1-20. (canceled)
 21. A method of treating heart failure with preservedejection fraction in a subject having heart failure with preservedejection fraction, the method comprising administering to the subject atherapeutically effective amount of one or more prodrugs of monomethylfumarate comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, polymorph, hydrate, solvate, or co-crystal thereof:

wherein: R₁ is unsubstituted C₁-C₆ alkyl; L_(a) is substituted orunsubstituted C₁-C₆ alkyl linker, substituted or unsubstituted C₃-C₁₀carbocycle, substituted or unsubstituted C₆-C₁₀ aryl, substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S; and R₂ and R₃ either: (a) areeach, independently, H, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstitutedC₂-C₆ alkynyl, substituted or unsubstituted C₆-C₁₀ aryl, substituted orunsubstituted C₃-C₁₀ carbocycle, substituted or unsubstitutedheterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, and S, or substituted or unsubstitutedheteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, and S; or (b) together with the nitrogenatom to which they are attached, form a substituted or unsubstitutedheteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, and S or a substituted or unsubstitutedheterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, and S.
 22. The method of claim 1,wherein a pharmaceutical composition is administered to the subject,wherein said pharmaceutical composition comprises a therapeuticallyeffective amount of the one or more prodrug of monomethyl fumarate thatis shown to provide MMF plasma exposure comparable to dimethyl fumarate120 mg to 720 mg per day.
 23. The method of claim 1, wherein saidpharmaceutical composition comprises 210 mg to 1260 mg of the compound.24. The method of claim 1, wherein the one or more prodrugs ofmonomethyl fumarate are administered in combination with one or moresecond agents useful for treating heart failure,
 25. The method of claim24, wherein the second agent is selected from the group consisting of: adiuretic, an ACE-inhibitor, a beta-blocker, an angiotensin receptorblocker, isosorbide dinitrate, hydralazine, an angiotensinreceptor-neprilysin inhibitor, an aldosterone antagonist, a PDE5inhibitor, a statin, a neprilysin inhibitor, an aldosterone inhibitor,and an antitumor necrosis factor-alpha therapy.
 26. The method of claim25, wherein the second agent is the statin.
 27. The method of claim 21,wherein treating comprises reducing mortality or improving survival inthe subject having heart failure with preserved ejection fraction. 28.The method of claim 21, wherein treating comprises increasing maximummyocardial oxygen consumption in the subject.
 29. The method of claim28, wherein the maximum myocardial oxygen consumption is increased togreater than 14 mL/g/min.
 30. The method of claim 21, wherein treatingcomprises one or more of: reducing ventricular stiffness and improvingventricular relaxation in the subject.
 31. A method of treating heartfailure with preserved ejection fraction in a subject having heartfailure with preserved ejection fraction, the method comprisingadministering to the subject a therapeutically effective amount of oneor more prodrugs of monomethyl fumarate comprising a compound of Formula(III), or a pharmaceutically acceptable salt, polymorph, hydrate,solvate, or co-crystal thereof:

wherein: R₁ is unsubstituted C₁-C₆ alkyl;

is selected from the group consisting of:

X is N, O, S, or SO₂; Z is C or N; m is 0, 1, 2, or 3; n is 1 or 2; w is0, 1, 2, or 3; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R₆, R₇, R₈ andR₉ are each, independently, H, substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstitutedC₂-C₆ alkynyl or C(O)OR_(a); and R_(a) is H or substituted orunsubstituted C₁-C₆ alkyl; and either: (a) each R₁₀ is, independently,H, halogen, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl,substituted or unsubstituted C₃-C₁₀ carbocycle, substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S; or (b) two R₁₀ attached tothe same carbon atom, together with the carbon atom to which they areattached, form a carbonyl, substituted or unsubstituted C₃-C₁₀carbocycle, substituted or unsubstituted heterocycle comprising one ortwo 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S,or substituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S; or (c) twoR₁₀ attached to different atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted C₃-C₁₀ carbocycle,substituted or unsubstituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S, orsubstituted or unsubstituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O, and S.
 32. Amethod of treating heart failure with preserved ejection fraction in asubject having heart failure with preserved ejection fraction, themethod comprising administering to the subject a therapeuticallyeffective amount of one or more prodrugs of monomethyl fumaratecomprising a compound of Formula (Ib), or a pharmaceutically acceptablepolymorph, hydrate, solvate, or co-crystal thereof:

A⁻ is a pharmaceutically acceptable anion; R₁ is unsubstituted C₁-C₆alkyl; L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker,substituted or unsubstituted C₃-C₁₀ carbocycle, substituted orunsubstituted C₆-C₁₀ aryl, substituted or unsubstituted heterocyclecomprising one or two 5- or 6-member rings and 1-4 heteroatoms selectedfrom N, O, and S, or substituted or unsubstituted heteroaryl comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O,and S; R₃′ is substituted or unsubstituted C₁-C₆ alkyl; and either: (a)R₂ and R₃ are each, independently, H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted orunsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₆-C₁₀ aryl,substituted or unsubstituted C₃-C₁₀ carbocycle, substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S; or (b) R₂ and R₃, togetherwith the nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O, and S, or a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.
 33. The method of claim 32,wherein a pharmaceutical composition is administered to the subject,wherein said pharmaceutical composition comprises a therapeuticallyeffective amount of the one or more prodrug of monomethyl fumarate thatis shown to provide MMF plasma exposure comparable to dimethyl fumarate120 mg to 720 mg per day.
 34. The method of claim 32, wherein saidpharmaceutical composition comprises 210 mg to 1260 mg of the compound.35. The method of claim 32, wherein the one or more prodrugs ofmonomethyl fumarate are administered in combination with one or moresecond agents useful for treating heart failure.
 36. The method of claim35, wherein the second agent is selected from the group consisting of: adiuretic, an ACE-inhibitor, a beta-blocker, an angiotensin receptorblocker, isosorbide dinitrate, hydralazine, an angiotensinreceptor-neprilysin inhibitor, an aldosterone antagonist, a PDE5inhibitor, a statin, a neprilysin inhibitor, an aldosterone inhibitor,and an antitumor necrosis factor-alpha therapy.
 37. The method of claim32, wherein treating comprises reducing mortality or improving survivalin the subject having heart failure with preserved ejection fraction.38. The method of claim 32, wherein treating comprises increasingmaximum myocardial oxygen consumption in the subject.
 39. The method ofclaim 38, wherein the maximum myocardial oxygen consumption is increasedto greater than 14 mL/g/min.
 40. The method of claim 32, whereintreating comprises one or more of: reducing ventricular stiffness andimproving ventricular relaxation in the subject.